- Practical Synthesis of Fludarabine and Nelarabine
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A new practical synthesis strategy has been developed to access the β- d -arabinofuranosyl purine nucleosides fludarabine and nelarabine. In our approach, an ortho -alkyne benzoyl ester is transiently introduced as a neighbouring-participation group in Vorbrüggen glycosylation to afford the corresponding β-nucleoside exclusively. The latter was further removed efficiently by using freshly prepared Ph 3 PAuOTFA to give the corresponding 2′-OH nucleosides without transesterification. After reversion of the configuration of 2′-OH and deprotection, fludarabine and nelarabine were obtained in high yield and purity.
- Bai, Jiang,Ding, Haixin,Liu, Jiang,Ouyang, Wenliang,Shen, Chunyang,Xiao, Qiang
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p. 417 - 423
(2020/01/23)
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- Synthesis method of fludarabine phosphate
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The invention provides a synthesis method of fludarabine phosphate, and the synthesis route is as follows: with vidarabine as a starting raw material, fludarabine is obtained through upper protection,nitrification, fluorination denitration and deprotection, so that the fludarabine is prepared by adopting a brand-new synthesis route; meanwhile, by improving the process of phosphorylation and refining of fludarabine, the reaction time is shortened, the generation of by-products is reduced, and the product quality is improved. The method has the following advantages: 1, the initial raw materialis beta-configuration, isomer separation is avoided, and the yield is improved; raw materials are easy to obtain, the route is simple, and the price is low; 3, salification and column-passing purification and separation are avoided, so that the method is suitable for industrialization.
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Paragraph 0041-0043; 0056-0060
(2020/08/22)
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- Synthesis method of fludarabine and nelarabine
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The present invention discloses a synthesis method of fludarabine and nelarabine. The method is prepared from a ribofuranose derivative as a raw material, an o-alkynyl benzoate is introduced at a 2-position hydroxyl group to obtain a key glycosyl donor, the key glycosyl donor and purine bases are subjected to a coupling reaction using a Vorbruggen glycosylation reaction to highly efficiently construct beta-nucleoside bonds, under catalysis of a gold catalyst, 2'-position ester groups are selectively removed to obtain important furyl ribonucleotide, and a bare 2' hydroxyl group is then subjected to two-step reactions of hydroxyl inversion and deprotection to respectively obtain fludarabine and nelarabine. The synthesis strategy has characteristics of being simple in operation, simple and easy to obtain the raw materials, easy in separation of products, high in reaction yield, etc., and has relatively good prospects for popularization and application.
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- Enzymatic Synthesis of Therapeutic Nucleosides using a Highly Versatile Purine Nucleoside 2’-DeoxyribosylTransferase from Trypanosoma brucei
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The use of enzymes for the synthesis of nucleoside analogues offers several advantages over multistep chemical methods, including chemo-, regio- and stereoselectivity as well as milder reaction conditions. Herein, the production, characterization and utilization of a purine nucleoside 2’-deoxyribosyltransferase (PDT) from Trypanosoma brucei are reported. TbPDT is a dimer which displays not only excellent activity and stability over a broad range of temperatures (50–70 °C), pH (4–7) and ionic strength (0–500 mM NaCl) but also an unusual high stability under alkaline conditions (pH 8–10). TbPDT is shown to be proficient in the biosynthesis of numerous therapeutic nucleosides, including didanosine, vidarabine, cladribine, fludarabine and nelarabine. The structure-guided replacement of Val11 with either Ala or Ser resulted in variants with 2.8-fold greater activity. TbPDT was also covalently immobilized on glutaraldehyde-activated magnetic microspheres. MTbPDT3 was selected as the best derivative (4200 IU/g, activity recovery of 22 %), and could be easily recaptured and recycled for >25 reactions with negligible loss of activity. Finally, MTbPDT3 was successfully employed in the expedient synthesis of several nucleoside analogues. Taken together, our results support the notion that TbPDT has good potential as an industrial biocatalyst for the synthesis of a wide range of therapeutic nucleosides through an efficient and environmentally friendly methodology.
- Pérez, Elena,Sánchez-Murcia, Pedro A.,Jordaan, Justin,Blanco, María Dolores,Manche?o, José Miguel,Gago, Federico,Fernández-Lucas, Jesús
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p. 4406 - 4416
(2018/09/14)
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- Synthesis process of fludarabine base
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The invention provides a synthesis process of fludarabine base. The synthesis process comprises selecting raw materials, synthesizing an intermediate, and synthesizing fludarabine base. The synthesisprocess has the beneficial effects that the source of the raw materials is widely available, the cost of the raw materials is low, the synthesis process is suitable for large-scale production and hassimple synthesis steps, fewer harmful substances are discharged in synthesis, and the synthesis process is safe and environment-friendly, has good use effect and can be promoted.
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Paragraph 0012-0025
(2018/11/10)
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- The arsenolysis reaction in the biotechnological method of synthesis of modified purine β-D-arabinonucleosides
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We found a unique property of E. coli purine nucleoside phosphorylases to selectively perform the arsenolysis reaction of ribonucleosides in their active site without affecting β-D-arabinonucleosides. In the synthesis of modified β-D-arabinonucleosides from the corresponding ribonucleosides, the catalytical amount of sodium arsenate in the transglycosylation reaction provided a 95 to 98% conversion rate. Such an approach was shown to simplify the composition of the reaction mixtures and facilitate the isolation of the target nucleosides, particularly, vidarabine, fludarabine, and nelarabine.
- Konstantinova,Fateev,Miroshnikov
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p. 372 - 380
(2016/08/03)
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- Simple modification to obtain high quality fludarabine
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A simple and improved debenzylation process is described to obtain fludarabine in greater than 99.8% purity and 90-95% yield.
- Kshirsagar, Siddheshwar W.,Deshpande, Mangesh S.,Sonawane, Swapnil P.,Maikap, Golak C.,Gurjar, Mukund K.
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experimental part
p. 840 - 842
(2012/07/28)
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- Use of Citrobacter koseri whole cells for the production of arabinonucleosides: A larger scale approach
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Purine arabinosides are well known antiviral and antineoplastic drugs. Since their chemical synthesis is complex, time-consuming, and polluting, enzymatic synthesis provides an advantageous alternative. In this work, we describe the microbial whole cell synthesis of purine arabinosides through nucleoside phosphorylase-catalyzed transglycosylation starting from their pyrimidine precursors. By screening of our microbial collection, Citrobacter koseri (CECT 856) was selected as the best biocatalyst for the proposed biotransformation. In order to enlarge the scale of the transformations to 150 mL for future industrial applications, the biocatalyst immobilization by entrapment techniques and its behavior in different reactor configurations, considering both batch and continuous processes, were analyzed. C. koseri immobilized in agarose could be used up to 68 times and the storage stability was at least 9 months. By this approach, fludarabine (58% yield in 14 h), vidarabine (71% yield in 26 h) and 2,6-diaminopurine arabinoside (77% yield in 24 h), were prepared.
- Nóbile, Matías,Médici, Rosario,Terreni, Marco,Lewkowicz, Elizabeth S.,Iribarren, Adolfo M.
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p. 2182 - 2188
(2013/02/25)
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- THERAPEUTIC FOR HEPATIC CANCER
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A novel pharmaceutical composition for treating or preventing hepatocellular carcinoma and a method of treatment are provided. A pharmaceutical composition for treating or preventing liver cancer is obtained by combining a chemotherapeutic agent with an anti-glypican 3 antibody. Also disclosed is a pharmaceutical composition for treating or preventing liver cancer which comprises as an active ingredient an anti-glypican 3 antibody for use in combination with a chemotherapeutic agent, or which comprises as an active ingredient a chemotherapeutic agent for use in combination with an anti-glypican 3 antibody. Using the chemotherapeutic agent and the anti-glypican 3 antibody in combination yields better therapeutic effects than using the chemotherapeutic agent alone, and mitigates side effects that arise from liver cancer treatment with the chemotherapeutic agent.
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- METHOD FOR THE MANUFACTURE OF 2-FLUORO-ARA-ADENINE
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A method is described for the manufacture of pure 2-fluoro-ara-adenine of Formula (I) from 2-fluoro-ara-adenine triacetate using potassium carbonate (K2CO3), wherein the 2-fluoro-ara-adenine has a reduced dimer contents, as well as the compound 2-fluoro-ara-adenine having a dimer contents of ≤ 0,3 %.
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Page/Page column 9
(2010/12/17)
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- Anti-Claudin 3 Monoclonal Antibody and Treatment and Diagnosis of Cancer Using the Same
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Monoclonal antibodies that bind specifically to Claudin 3 expressed on cell surface are provided. The antibodies of the present invention are useful for diagnosis of cancers that have enhanced expression of Claudin 3, such as ovarian cancer, prostate cancer, breast cancer, uterine cancer, liver cancer, lung cancer, pancreatic cancer, stomach cancer, bladder cancer, and colon cancer. The present invention provides monoclonal antibodies showing cytotoxic effects against cells of these cancers. Methods for inducing cell injury in Claudin 3-expressing cells and methods for suppressing proliferation of Claudin 3-expressing cells by contacting Claudin 3-expressing cells with a Claudin 3-binding antibody are disclosed. The present application also discloses methods for diagnosis or treatment of cancers.
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- Enzymatic transglycosylation of natural and modified nucleosides by immobilized thermostable nucleoside phosphorylases from Geobacillus stearothermophilus
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Natural and modified purine nucleosides have been synthesized using the recombinant thermostable enzymes purine nucleoside phosphorylase II (E. C. 2.4.2.1) and pyrimidine nucleoside phosphorylase (E. C. 2.4.2.2) from Geobacillus stearothermophilus B-2194. The enzymes were produced in recombinant E. coli strains and covalently immobilized on aminopropylsilochrom AP-CPG-170 after heating the cell lysates and the removal of coagulated thermolabile proteins. The resulting preparations of thermostable nucleoside phosphorylases retained a high activity after 20 reuses in nucleoside transglycosylation reactions at 70-75°C with a yield of the target products as high as 96%. Owing to the high catalytic activity, thermal stability, the ease of application, and the possibility of repeated use, the immobilized preparations of thermostable nucleoside phosphorylases are suitable for the production of pharmacologically important natural and modified nucleosides.
- Taran,Verevkina,Feofanov,Miroshnikov
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experimental part
p. 739 - 745
(2010/08/07)
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- F-ara-AMP is a substrate of cytoplasmic 5′-nucleotidase II (cN-II): HPLC and NMR studies of enzymatic dephosphorylation
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Intracellular accumulation of triphosphorylated derivatives is essential for the cytotoxic activity of nucleoside analogues. Different mechanisms opposing this accumulation have been described. We have investigated the dephosphorylation of monophosphorylated fludarabine (F-ara-AMP) by the purified cytoplasmic 5′-nucleotidase cN-II using HPLC and NMR. These studies clearly showed that cN-II was able to convert F-ara-AMP into its non phosphorylated form, F-ara-A, with a K m in the millimolar range and V max = 35 nmol/min/mg, with both methods. Cytoplasmic 5′-nucleotidase cN-II can degrade this clinically useful cytotoxic nucleoside analogue and its overexpression is thus likely to be involved in resistance to this compound. Copyright Taylor & Francis Group, LLC.
- Jordheim, Lars,Cros, Emeline,Galmarini, Carlos,Dumontet, Charles,Bretonnet, Anne-Sophie,Krimm, Isabelle,Lancelin, Jean-Marc,Gagnieu, Marie-Claude
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p. 289 - 297
(2007/10/03)
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- A process for the preparation of fludarabine phosphate from 2-fluoroadenine
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The invention provides a process for the preparation of fludarabine phosphate from 2-fluoroadenine and 9-β-D-arabinofuranosyl-uracil usingEnterobacter aerogenes (EBA). 2-Fluoroadenine is reacted with 9-β-D-arabinosyl-uracile in a water solution at pH = 7 in the presence of EBA cell paste, to yield fludarabine. Fludarabine is then treated with acetic anhydride and the resulting acetylderivative is crystallised and hydrolysed to fludarabine. Phosphorylation and crystallisation afford fludarabine phosphate.
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- LIPID CLEAVAGE ENZYME
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A membranous enzyme not yet described in the state-of-the-art can be extracted from cellular membrane fractions of blood leukocytes or monocytes/macrophages. Also disclosed is the use of substrates of this enzyme to prepare medicaments that contain these substrates as pharmaceutical active substance. These medicaments are useful to direct pharmacologically active substances to target cells and to enrich target cells with said substances. Also disclosed are in-vitro research systems containing this enzyme used to detect other substrates of this enzyme.
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- Process for the preparation of fludarabine or fludarabine phosphate from guanosine
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A process for the production of fludarabine or fludarabine phosphate is provided, wherein the nucleoside guanosine or a suitable derivative is employed as the starting material. The guanosine starting material is subjected to (a) conversion of the 6-keto group into a 6-amino group, (b) conversion of the 2-amino group to a 2-fluoro group, and (c) conversion of the ribofuranosyl moiety to an arabinofuranosyl moiety. Steps (a), (b), and (c) can be performed individually or concomitantly and in any sequence.
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- Arabinosyl-2-fluoroadenine augments cisplatin cytotoxicity and inhibits cisplatin-DNA cross-link repair
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Cytotoxicity was increased significantly when arabinosyl-2-fluoroadenine (F-ara-A) was administered in simultaneous combination with cisplatin (CDDP) to human colon tumor cell lines relatively sensitive (LoVo) or resistant (CP2.0) to CDDP. Because the mechanism of action of F-ara-A indicates that it may be an effective inhibitor of DNA repair, we hypothesized that F-ara-A induces cytotoxic augmentation by suppressing cellular repair in CDDP- damaged DNA lesions. To test this, we compared the repair of CDDP-induced DNA interstrand cross-links in the total genome and in ERCC1 gene-specific sequences of LoVo and CP2.0 cells for treatments with CDDP and CDDP plus F- ara-A. We determined the DNA repair by measuring the rate of removal of the cross-links, using two methods, i.e., an ethidium bromide fluorescence binding assay, which detects the DNA lesion in the total genome, and a method combining denaturation/renaturation neutral agarose gel electrophoresis and Southern hybridization to detect gene-specific lesions. When F-ara-A (15 μM) was coadministered with CDDP (15 μg/ml for LoVo cells and 30 μg/ml for CP2.0 cells) for 4 hr, the initial cross-link index for the total genome was increased 67% (4.5 versus 2.7 with CDDP alone) in LoVo cells and 93% (2.9 versus 1.5 with CDDP alone) in resistant CP2.0 cells. At 10 hr after the treatment, only 5% of the cross-links had been removed in combination- treated LoVo cells, compared with 40% in CDDP-treated LoVo cells; in CP2.0 cells, F-ara-A inhibited the removal of cross-links from 95% to 45%. Similar results were obtained for ERCC1 gene-specific DNA sequences. These data suggest that F-ara-A enhances the accumulation of CDDP-induced cross-links in LoVo and CP2.0 cells by suppressing the repair of such lesions, thereby enhancing the cytotoxicity of CDDP in combination treatment.
- Yang, Li-Ying,Li, Lan,Keating, Michael J.,Plunkett, William
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p. 1072 - 1079
(2007/10/03)
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- Hydrogenation of 2-fluoro-9-(2,3,5-tri-o-benzyl-beta-D-arabinofuranosyl)adenine
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A process for the preparation of 2-fluoro-9-beta-D-arabinofuranosyl purine (VII) by a reaction of palladium chloride and hydrochloric acid with 2-fluoro-9-(2,3,5-tribenzyl-beta-D-arabinofuranosyl)adenine (VI) at elevated pressures in a solvent for (VI) is described. The reaction is rapid, economical and efficient.
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- 6-azido-2-fluoropurine, useful in the synthesis of nucleosides
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This invention pertains to novel methods of synthesizing fludarabine, fludarabine phosphate and related nucleoside pharmacologic agents utilizing 6-azido-2-fluoropurine as a novel intermediate. In particular this invention pertains to a synthesis of fludarabine where the relatively low yield fluorination step is done before the costly coupling step.
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- Process for the preparation of 2-amino-9-(2,3,5-tri-O-benzyl-beta-D-arabinofuranosyl) adenine and novel intermediates
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A process for the preparation of 2,6-diamino-9-(2,3,5-tri-O-benzyl-beta-D-arabinofuranosyl)purine (V) by reacting 2,6-di(alkoxyacetamido)purine (II) with 2,3,5-tri-O-benzyl-1-chloro-alpha-D-arabinofuranose (III) to produce 2,6-di(alkoxyacetamido)-9-(2,3,5-tri-O-benzyl-beta-D-arabinofuranosyl)purine (IV) and then deprotecting the 2,6-positions to produce the 2,6-diamine (V) is described. The process provides purine (V) in high yield. Purine (V) is an intermediate in the preparation of 9-beta-D-arabinofuranosyl-2-fluoroadenine which is a cytotoxic agent.
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- Prodrug derivatives of 9β-D-arabinofuranosyl-2-fluoroadenine
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The 5'-formate and the 5'-phosphate derivatives of 9-β-D-arabinofuranosyl-2-fluoroadenine have been prepared as prodrug forms of the anti-cancer agent 9-β-D-arabinofuranosyl-2-fluoroadenine, known as F-ara-A. These derivatives are quite water soluble whereas F-ara-A itself is sparingly soluble in water or in any organic solvents. Delivery of these prodrug forms to mice with L1210 leukemia results in the formation of higher levels of the triphosphate of F-ara-A, the active form of the drug, in the target L1210 leukemia cells. These prodrug forms are much more active chemotherapeutically than 9-β-D-arabinofuranosyladenine, known as ara-A, and equivalent in activity to the combination of ara-A and 2'-deoxycoformycin, known as 2'-dCF, an effective in vivo inhibitor of adenosine deaminase, a ubiquitous enzyme that destroys ara-A in vivo.
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- Anticancer and antiviral activity of 9-β-D-arabinofuranosyl-2-fluoroadenine
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A method of utilizing 9-β-D-arabinofuranosyl-2-fluoroadenine, known as 2-F-AraA (NSC 118218), in the treatment of murine leukemia and as an antiviral agent for DNA viruses, such as DNA viruses Herpes Simplex Virus Type I and Vaccinia virus grown in H.Ep-2 cells in culture. An operable dosage for utilization of 2-F-AraA is a treatment span of 1-10 days with the dosage 2-8 times per day at 8-400 mg/kg/dose. It has been further found that a single dosage on days 1, 5, and 9 based on a 10-day treatment schedule gave satisfactory results.
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- Procedure for the preparation of 9-β-D-arabinofuranosyl-2-fluoroadenine
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The present invention is an improved multi-step process for the production of 9-β-D-arabinofuranosyl-2-fluoroadenine (2-F-AraA) and an improvement over the process of Montgomery and Hewson, J. Med. Chem., 12:498 (1969). This compound is an important tool in antitumor therapy and has shown activity against leukemia L1210 and P388 in animals as well as being a potent antiviral agent. Its therapeutic effectiveness occurs because 2-F-AraA is not a substrate for adenosine deaminase which vitiated against the activity of the parent compound 9-β-D-arabinofuranosyladenine (araA) as indicated in experimental animal cancers.An advantage of making 2-F-AraA by the present process is that there is a sharply increased yield based on the chlorosugar up to about 400 percent. In the present improved process the differences lie in utilizing as a reactant 2,4,5,6-tetraaminopyrimidine; the acetylation of 2-aminoadenine in acetic acid and pyridine; the reaction of 2,6-diacetamidopurine with chlorosugar in ethylene chloride in the presence of a molecular sieve and subsequent deacetylation with methanolic sodium methoxide. Further, the diazotization step is carried out in a homogenous mixture of tetrahydrofuran and fluoboric acids. Finally, the O-benzyl groups are removed by the use of boron trichloride in ether.
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